The molecular profile of luminal B breast cancer

Abstract

Molecular profiling studies have found that estrogen receptor-positive (ER+) human breast cancers are comprised of at least two distinct diseases with differing biologies. With the advent of DNA microarrays, global gene expression patterns were used to define the luminal A and luminal B subtypes of ER+ breast cancer, with luminal B cancers showing a more aggressive phenotype including substantially worse outcomes in patients. The luminal B subtype designation could be considered a surrogate for those ER+ tumors having low progesterone receptors, high proliferation, high grade, and predicted poor response to hormone therapy. While they express estrogen receptors, luminal B cancers do not show a corresponding expression of estrogen-regulated genes, and may therefore rely upon alternative pathways for growth. At the molecular level, luminal B cancers appear dramatically distinct from luminal A cancers, at the levels of gene expression, gene copy, somatic mutation, and DNA methylation; luminal B cancers are also genetically and genomically altered to a greater extent than luminal A cancers. While, in the clinical setting, luminal B is typically regarded as an ER+, hormone-sensitive disease, more research is needed into how to better treat it. Comprehensive profiling initiatives, such as The Cancer Genome Atlas, have recently provided us a catalog of mutated or copy altered genes, from which new therapeutic targets could potentially be mined. Candidate pathways that might be targeted in luminal B include those involving growth factor receptors, including HER2 and EGFR, as well as PI3K/Akt/mTor.

Keywords: TCGA; breast cancer; integrative analysis; luminal B; molecular profiling.

Figure 1

Luminal B breast cancer is associated with substantially worse patient outcomes. (A) Expression patterns of the PAM50 gene set (41 genes represented on the U133A array platform) in the mRNA profile datasets from Hoadley et al, (N = 247) and Kessler et al. U133A compendium (N = 1340, representing nine separate studies). Using the PAM50 genes and the Hoadley subtype assignments, inter-profile correlations between the Hoadley and Kessler datasets were used to assign mRNA-based subtypes (basal-like, HER2-enriched, normal-like, luminal A, luminal B) to the Kessler profiles. (B) Kaplan–Meier plot of distant metastasis-free survivals for the mRNA-based subtypes. Survival capped at 20 years.

Figure 2

The luminal B subtype represents both ER+ breast cancer with low PR levels and ER+ breast cancer with predicted worse outcome. Notes: For tumor profiles in the Kessler compendium, corresponding mRNA levels for ER, PR, and HER2 are shown. In addition, the tumors were scored for predicted outcome, using the genes in the OncotypeDX and MammaPrint diagnostic assays (scores computed by adding the normalized values for the positively weighted genes and subtracting the values for the negatively weighted genes). Abbreviations: ER+ estrogen receptor-positive; PR, progesterone receptor; ER, estrogen receptor.

Figure 3

The (mRNA-based) luminal B breast cancer subtype is reflected in alternative classifications of breast cancer, based on molecular profiling at levels of microRNA, methylation, and protein. Notes: Data are from TCGA of 547 human breast tumors profiled for gene expression and subtyped for mRNA-based classification. Most all of these tumors were profiled on other platforms for microRNA, DNA methylation, and protein (RPPA). By each of the other platforms, unsupervised clustering classified the tumors into distinct subtypes; more detail on these alterative classifications is provided in the TCGA breast study. Shown here is the significance of overlap between each of the mRNA-based subtypes and the subtypes based on the other platforms (bright yellow, highly significant enrichment, with ±2 roughly corresponding to a nominal two-sided significance of P < 0.05). Abbreviations: TCGA, The Cancer Genome Atlas; RPPA, reverse-phase protein array.

Figure 4

Luminal B cancers are genetically and genomically altered to a greater extent than luminal A cancers (and comparable to the ER− subtypes). Notes: Top panel shows box plot for the numbers of nonsilent somatic mutations for each mRNA-based subtype. Bottom panel shows box plot of the variation from normal copy levels for each subtype (taking the standard deviation across all genes in the profile of the tumor:normal log-ratio values). Data are from TCGA (top panel, N = 506 tumors with somatic mutation and expression data; bottom panel, N = 484 tumors with mutation, expression, and LOH data). Abbreviations: ER−, estrogen receptor-negative; TCGA, The Cancer Genome Atlas; LOH, loss of heterozygosity.

Figure 5

Luminal B cancers have distinct patterns of alterations in genes impacting key pathways including p53, PI3K, Rb, and MAP kinase. Notes: For selected genes, the percentage of tumors, by mRNA-based subtype, altered by somatic mutation (top panel) or by LOH (bottom panel). Data are from TCGA (top panel, N = 506 tumors with somatic mutation and expression data; bottom panel, N = 484 tumors with mutation, expression, and LOH data). Abbreviations: LOH, loss of heterozygosity; TCGA, The Cancer Genome Atlas.

Figure 6

Two different models to explain the possible origin of the breast cancer subtypes (including luminal B). (A) “Linear evolution” model, whereby cancer cells or cancer precursor cells gradually evolve (by accumulation of genomic alterations) from a luminal A or normal-like subtype (with ER/PR expression), to a luminal B subtype (with loss of PR and possible gain of growth factor receptor, or GFR signaling), to either a HER2-enriched or Basal-like subtype (with complete loss of ER signaling and increase of GFR signaling). (B) “Distinct pathways of progression” model, whereby each breast cancer subtype follows a path of initiation and progression that is independent of that of the other subtypes. Abbreviations: ER, estrogen receptor; PR, progesterone receptor; GFR, growth factor receptor.